Atrial natriuretic peptide secretion in heart transplant patients

Plasma atrial natriuretic peptide (ANP), plasma renin activity (PRA), aldosterone (ALD) and vasopressin (VP) were assessed in six heart transplant patients (HTP) and ten healthy subjects under bed rest conditions and 60 and 120 minutes after head-out water immersion (WI). Bed rest had no significant influence on these parameters. WI raised plasma volume (PV) to the same extent in both groups. This increase of PV was accompanied by significant suppression of PRA, ALD and VP and an increase of plasma ANP. In HTP basal plasma ANP was significantly elevated and the ANP response to central hypervolemia reduced. Significantly elevated VP plasma levels were also found in HTP. These endocrine abnormalities in HTP seem to be caused by latent failure of the transplanted heart. No direct correlation was found between plasma ANP and PRA, ALD and VP under basal conditions and after WI in either HTP or normals.     

Plasma atrial natriuretic peptide in cardiac transplant recipients. A prospective study

Cardiac transplantation in 10 patients with congestive heart failure resulted in reduction of high plasma concentrations of atrial natriuretic peptide (ANP), preoperatively five-fold above normal, to a level two-fold above normal, which was maintained throughout a 12-week follow-up period. Cardiac function was normalized in all patients. Transient increases in plasma ANP, in four cardiac recipients 3-10-fold their basal levels, could neither be related to rejection episodes nor to cardiac dysfunction, but rather to signs of fluid and sodium retention. High plasma ANP levels in cardiac transplant recipients suggest that the capacity to secrete ANP is preserved in the transplanted heart.     

Plasma levels of atrial natriuretic peptide at rest and during exercise in heart failure--influence of cardiac rhythm and haemodynamics.

The relationship between plasma levels of immunoreactive atrial natriuretic peptide (ir-ANP), arginine vasopressin (AVP), cardiac rhythm and different haemodynamic variables were studied at rest and during exercise in 16 patients with heart failure undergoing heart catheterization for clinically indicated reasons. Even though there was no significant relationship between pulmonary capillary wedge pressure (PCW) and ir-ANP at rest (r = 0.39; P = 0.14) changes in these variables with exercise correlated well (r = 0.71; P = 0.002). Change in right atrial mean pressure, heart rate, mean arterial blood pressure or cardiac index did not significantly influence change in plasma levels of ir-ANP. The correlation between PCW and AVP at rest (r = 0.92; P less than 0.001) disappeared during exercise. Calculated ir-ANP/PCW ratios decreased slightly during exercise, but were not influenced by initial atrial pressures or atrial fibrillation. These observations provide evidence for a similar responsiveness of ANP in patients with sinus rhythm and atrial fibrillation. The ability of rapid change in ANP plasma levels during exercise was preserved and proportional to changes in PCW over a wide pressure range in the studied patient group. This finding indicates that left atrium distension rather than right atrium distension is the major determinant for the release of ANP in patients with congestive heart failure. The observed rapid responsiveness of ANP to change in left atrial pressure may allow the hormone to modulate haemodynamic response during short periods of exercise.     

Effect of ryanodine on atrial natriuretic peptide secretion by contracting and quiescent rat atrium

To elucidate the mechanism involved in the release of atrial natriuretic peptide (ANP), we studied the importance of ryanodine-sensitive Ca²⁺ release in stretch-secretion coupling. The experiments were made with a left atrial preparation, where the stretch of myocytes was induced by changing the intra-atrial pressure. When external pacing was not applied, the atrial preparation was not spontaneously contracting, and it was therefore possible to investigate the secretory mechanism in the quiescent atrium. The superfusate was collected in 2-min fractions and assayed for ANP immunoreactivity. Filtration analysis revealed that the major fraction in the superfusate in all experimental situations had a similar molecular weight as the ANP 1–28. Ryanodine (1.0 M and 0.1 M) inhibited stretch-stimulated ANP secretion dose dependently both in paced and nonpaced atrium, but did not have any effect on basal secretion. The present results support the notion that intracellular Ca²⁺ transients from the intracellular stores are essential for stretch-stimulated ANP secretion, independently from excitation and contraction. Basal ANP secretion is not inhibited by blocking ryanodine-sensitive Ca²⁺ channels, either in contracting or in non-contracting atria. In addition our results confirm that the principal stimulus for ANP secretion in response to atrial distension is the stretch of myocytes. Length shortening of myocytes is not essential for ANP release.     

Short-term exercise training improves diaphragm antioxidant capacity and endurance

These experiments tested the hypothesis that short-term endurance exercise training would rapidly improve (within 5 days) the diaphragm oxidative/antioxidant capacity and protect the diaphragm against contraction-induced oxidative stress. To test this postulate, male Sprague-Dawley rats (6 weeks old) ran on a motorized treadmill for 5 consecutive days (40–60 min · day⁻¹) at approximately 65% maximal oxygen uptake. Costal diaphragm strips were excised from both sedentary control (CON, n=14) and trained (TR, n=13) animals 24 h after the last exercise session, for measurement of in vitro contraction properties and selected biochemical parameters of oxidative/antioxidant capacity. Training did not alter diaphragm force-frequency characteristics over a full range of submaximal and maximal stimulation frequencies (P > 0.05). In contrast, training improved diaphragm resistance to fatigue as contraction forces were better-maintained by the diaphragms of the TR animals during a submaximal 60-min fatigue protocol (P < 0.05). Following the fatigue protocol, diaphragm strips from the TR animals contained 30% lower concentrations of lipid hydroperoxides compared to CON (P < 0.05). Biochemical analysis revealed that exercise training increased diaphragm oxidative and antioxidant capacity (citrate synthase activity +18%, catalase activity +24%, total superoxide dismutase activity +20%, glutathione concentration +10%) (P < 0.05). These data indicate that short-term exercise training can rapidly elevate oxidative capacity as well as enzymatic and non-enzymatic antioxidant defenses in the diaphragm. Furthermore, this up-regulation in antioxidant defenses would be accompanied by a reduction in contraction-induced lipid peroxidation and an increased fatigue resistance. Accepted: 6 August 1999     

Effects of short-term endurance exercise training on vascular function in young males

We investigated effects of 6 days of endurance exercise training [cycling at 65% of peak oxygen consumption (VO_2peak) for 2 h a day on six consecutive days] on vascular function in young males. Measures of VO_2peak, arterial stiffness, calf vascular conductance and heart rate variability were obtained pre- and post-training. Indices of arterial stiffness were obtained by applanation tonometry to determine aortic augmentation index normalized to a heart rate of 75 bpm (AI _x @75 bpm), and central and peripheral pulse wave velocity (CPWV, PPWV). Resting and maximal calf vascular conductances were calculated from concurrent measures of blood pressure and calf blood flow using venous occlusion strain-gauge plethysmography. Time and frequency domain measures of heart rate variability were obtained from recording R–R intervals during supine and standing conditions. Both CPWV (5.9 ± 0.8 vs. 5.4 ± 0.8 m/s) and PPWV (9.7 ± 0.8 vs. 8.9 ± 1.3 m/s) were reduced following the training program. No significant changes were observed in AI _x @75 bpm, vascular conductance, heart rate variability or VO_2peak. These data indicate that changes in arterial stiffness independent of changes in heart rate variability or vascular conductance can be achieved in healthy young males following only 6 days of intense endurance exercise.     

Atrial natriuretic peptide response to endurance physical training in the rat

Summary The effect of an endurance physical training programme on the plasma and atrial natriuretic peptides (ANP) and on renal glomerular ANP receptors was evaluated in male normotensive Wistar rats. Maximal O₂ uptake was significantly greater in the endurance trained (117.1 Ml O₂ · kg^–1 · min^–1, SEM 6.18 versus the control rats 84.2 ml O₂ · kg^–1 · min^–1, SEM 4.88, P<0.01. In addition, various muscle oxidative enzymes were also significantly higher in endurance trained animals. An increase in resting plasma [ANP] was observed after 11 weeks of physical training (40.02 pg · ml^–1, SEM 7.07 vs 22.8 pg.ml^–1, SEM 3.83, P<0.05). Glomerular ANP receptor density was lower in trained rats (272 fmol · mg^–1 protein, SEM 3.1 vs 380 fmol · mg^–1 protein, SEM 6.1, P < 0.05), whereas atrial tissue [ANP] was not significantly different between controls and trained animals. However, in trained rats, circulating [ANP] was closely correlated with left atrial [ANP] (r = –0.92, P<0.05). Resting systolic blood pressure had not changed at the end of this physical training programme. It is considered that under physiological conditions ANP may be involved in long-term extracellular fluid volume homeostasis through the regulation of renal glomerular ANP receptors, and that the left atrium might play a significant role in this long term fluid volume control.     

Increase in atrial natriuretic peptide in response to physical exercise

Summary Circulating atrial natriuretic peptide (ANP) level was determined during physical exercise to investigate the correlation between changes in ANP level and heart rate increases.Six subjects exercised at a work level of 75% for 30 min, two also performed two successive exercises at 75% while two more exercised for longer at 55% · Plasma ANP levels and heart rate increased in all the exercising subjects. At the end of the exercise, the ANP level fell immediately, suggesting an immediate reduction in ANP secretion by the heart. Pre-exercise values were reached after 30 min. Successive exercises gave the same heart rate related ANP patterns without previous secretory episodes having any effect. These results lead to the conclusion that ANP intervenes in the cardiovascular adjustments to exercise.     

Changes in plasma atrial natriuretic peptide during exercise in healthy volunteers

Graded exercise was performed in three healthy volunteers. Plasma levels of immunoreactive atrial natriuretic peptide (iANP) were determined at different workloads. Unchanged or slightly decreased plasma levels of iANP were observed during light exercise, whereas at medium to high workloads a considerable increase in plasma levels of iANP was found. Factors responsible for the increase in plasma levels of iANP might include elevated right atrial pressure and increased plasma levels of epinephrine and norepinephrine.     

Atrial natriuretic factor during exercise in male endurance athletes: effect of training

Nine male endurance runners were evaluated with bicycle exercise testing before a training break of 3 weeks duration, and 0, 2 and 4 weeks after resumption of training to assess the effects of training on resting and exercise plasma atrial natriuretic factor (ANF) measured at 50% and 100% of predetermined maximal workload. Maximal oxygen uptake and lean body mass (LBM) were calculated at each time point. Maximal oxygen uptake decreased during training break, but rose 4 weeks after resumption of training (P less than 0.01). LBM was unchanged after inactivity, but rose after resumption of training (P less than 0.01). Plasma ANF at rest did not change throughout the experiment. ANF levels rose after training break at maximal workload (P less than 0.05), and decreased 4 weeks after resumption of training, but only at submaximal workload (P less than 0.05). No correlations between systolic blood pressure, mean blood pressure or heart rate and ANF could be demonstrated. These results indicate that the haemodynamic changes associated with endurance training are reflected in plasma ANF levels during exercise, but not at rest. The full adaptation of ANF release to training probably requires more time than the 4 weeks reported for the haemodynamic adjustments.     

The heart rate response to exercise and circulating catecholamines in heart transplant recipients

The plasma concentration of noradrenaline ([NA]) is higher than that of adrenaline ([A]) both in normal subjects and in heart transplant recipients (HTR). Since in both groups the myocardial density of beta1-adrenergenic receptors is much greater than that of beta2-adrenergenic receptors, the chronotropic response of a denervated heart to changes in plasma [NA] and [A] in the absence of reinnervation should be similar to that of agonist stimulation of beta1-receptors. To test this hypothesis, 17 HTR and 9 healthy subjects (CTL) performed incremental exercise on a cycle ergometer to voluntary exhaustion. Heart rate (HR) was recorded by electrocardiography. [NA] and [A] were measured by high-pressure liquid chromatography at rest and at increasing workloads (w). In both groups, HR and [NA+A] increased with w, and HR with [NA+A]. Normalized HR values, plotted against the logarithm of [NA+A], fitted significantly logistic curves. The affinity constants were different, i.e. 2599+/-350 and 487+/-37 ng.l(-1), for HTR and CTL, respectively. The chronotropic effect of changes in [NA+A] in HTR was similar to that of combined beta1- and beta2-adrenergic activation evoked by applying isoprenaline to isolated heart myocytes (Brodde OE, Pharmacol Ther 60:405-430, 1993). These findings suggest that over time sympathetic reinnervation and the modulation of beta-receptors may take place in HTR, ruling out the hypothesis of persistent heart denervation.     

Left ventricular torsion and untwisting during exercise in heart transplant recipients

Left ventricular (LV) rotation is the dominant deformation during relaxation and links systole with early diastolic recoil. LV torsion and untwisting rates during submaximal exercise were compared between heart transplant recipients (HTRs), young adults and healthy older individuals to better understand impaired diastolic function in HTRs. Two dimensional and colour M-mode echocardiography with speckle-tracking analysis were completed in eight HTRs (age: 61 ± 9 years), six recipient age-matched (RM, age: 60 ± 11 years), and five donor age-matched (DM, age: 35 ± 8 years) individuals (all males) at rest and during submaximal cycle exercise. LV peak torsion, peak rate of untwisting and peak intraventricular pressure gradients (IVPGs) were examined. LV torsion increased with exercise in DMs (6.5 ± 5.6 deg, P < 0.05), but not in RMs (−2.6 ± 7.0 deg) or HTRs (−0.9 ± 4.4 deg). The change from rest to exercise in the peak rate of untwisting was significantly greater for DMs (−2.1 ± 0.5 rads s⁻¹, P < 0.05) compared to RMs (−0.7 ± 1.3 rads s⁻¹) and HTRs (−0.2 ± 0.9 rads s⁻¹). The amount of untwisting occurring prior to mitral valve opening substantially declined with exercise in RMs and HTRs only. The change in IVPGs was 1.3-fold greater in DMs versus HTRs or RMs ( P > 0.05). Peak LV torsion and untwisting are blunted during exercise in HTRs and RMs compared to DMs. These factors may contribute to the impaired diastolic filling found in HTRs during exercise. Similarities between HTRs and RMs during exercise suggest functional accelerated ageing of the cardiac allograft.     

Age-related heart rate response to exercise in heart transplant recipients. Functional significance

The heart rate (HR) and O(2) uptake (VO(2)) responses to cycle ergometer exercise and the role of O(2) transport in limiting submaximal and maximal aerobic performance were assessed in 33 heart transplant recipients (HTR) [14 children (P-HTR), 11 young adults (YA-HTR) and 8 middle-age adults (A-HTR)] and in 28 age-matched control subjects (CTL). In 7 P-HTR ("responders") the HR response to the onset of exercise (on-response) was as fast as that of CTL, whereas in all other patients ("non-responders") the HR on-response was typical of the denervated heart. Compared with non-responder P-HTR, responder P-HTR were also characterized by a normal peak HR (177+/- 16 vs. 151+/- 25 beats/min), an equally slow time constant for the VO(2) on-response (tau: 54 +/- 11 vs. 62+/- 13 s) and a similar low (approximately 60% of that of CTL) peak VO(2) (28 +/- 7 vs. 26 +/- 10 ml/kg per min). On the other hand non-responder YA-HTR and A-HTR were characterized by a relatively low peak HR (151 +/- 21 and 144 +/- 29 beats/min, respectively), a slow tau for the on-response (63 +/- 12 and 70 +/- 11 s) and a low peak (28 +/- 7 and 19 +/- 6 ml/kg per min). In conclusion, a sizeable number of paediatric patients (responder P-HTR) may reacquire the normal HR response to exercise, both in terms of kinetics and maximal level. Despite the almost complete recovery of cardiovascular function, and, probably, oxygen delivery, both the kinetics of the VO(2) on-response and the maximal aerobic power of the responder P-HTR were similar to those of non-responder P-HTR. The latter finding is probably attributable to peripheral limitations, due to inborn and/or pharmacological muscle deterioration.     

Effect of inhaled atrial natriuretic peptide on methacholine bronchoconstriction in asthma

We have previously demonstrated that intravenous and inhaled atrial natriuretic peptide (ANP) significantly inhibits histamine induced bronchoconstriction in asthmatic patients. The current study was designed to determine whether inhaled ANP was also able to inhibit the effects of methacholine. Eight atopic asthmatic patients (five women) were studied: mean (SD) age 38.2 (8.3) years flow expiratory volume per second (FEV₁) 2.97 (0.60) litres, equivalent to 92 (13) % of the predicted. Each had demonstrated at least mild bronchial hyperreactivity to inhaled methacholine at screening (geometric mean PC20 l.02mg/ml; range 0.1l–6.54mg/ml). Patients attended for 3 study days and after baseline spirometry received 3.5 ml saline (placebo), 0.1 mg ANP or 1 mg ANP (ANP dissolved in 3.5ml saline) in a randomized, double-blind manner via a Mizer aerosol conservation device. Aerosolization took approximately 9 min and FEV₁ was repeated at 0.5, 1.5 and 3 min after completion. Immediately thereafter each patient received a 2 min inhalation of methacholine at a dose individually calculated to give a 25% fall in FEV₁ (as extrapolated at their initial screening visit) and the FEY₁ was followed over the next 20 min. Mean (SEM)% FEV₁ did not change significantly after ANP being -4.3 (1.7), -3.2 (2.7) and -2.4 (1.2) after placebo, 0.1 mg ANP and 1 mg ANP respectively. The mean (SEM) maximum fall in FEV₁ after methacholine was as follows: placebo 26.9 (5.7)%, 0-1 mg ANP 18.2 (4.3)% and 1.0mg 11.2(2 7)%, (P < 0.05 placebo vs 1 mg ANP). These results demonstrate that ANP offers significant protection against methacholine induced bronchoconstriction in asthmatic patients.     

Effect of beta 1-adrenoceptor blockade on plasma levels of atrial natriuretic peptide during exercise in normal man

Increased plasma levels of atrial natriuretic peptide (ANP) during exercise have been reported. To investigate the role of tachycardia as a stimulus for release of ANP during exercise the following study was undertaken. Graded exercise was performed in six healthy volunteers before and after beta 1-adrenoceptor blockade. Plasma levels of ANP were determined at different workloads in both cases. At rest and at all workloads during exercise plasma levels of ANP were higher after beta 1-adrenoceptor blockade than without. Therefore, it is unlikely that tachycardia is a major stimulus for secretion of ANP during exercise. It is suggested that increased right atrial pressure and/or pulmonary arterial blood pressure and increased plasma levels of catecholamines are important secretory stimuli for ANP during exercise.     

Atrial natriuretic peptide and atrial pressure in patients with congestive heart failure

To define the relation between atrial pressures and the release of atrial natriuretic peptide, we measured plasma concentrations of the peptide in 26 patients with cardiac disease--11 with normal atrial pressures and 15 with elevated atrial pressures (11 of these 15 had elevated pressures in both atria). Mean peptide levels (+/- SEM) in the peripheral venous blood were increased in the 11 patients with cardiac disease and normal atrial pressures, as compared with 60 healthy controls (48 +/- 14 vs. 17 +/- 2 pmol per liter). In the patients with elevated atrial pressures, peptide concentrations were increased twofold in peripheral venous, right atrial, pulmonary arterial, and systemic arterial plasma, as compared with the concentrations in the patients with normal atrial pressures. A step-up in peptide concentration was seen between the venous and right atrial plasma (P less than 0.002) and between the pulmonary and systemic arterial plasma (P less than 0.01), suggesting release of the peptide from the atria. A linear relation was found between right atrial pressure and right atrial peptide concentration (r = 0.835, P less than 0.001) and between pulmonary wedge pressure and the systemic arterial peptide concentration (r = 0.866, P less than 0.001). Right atrial pressure and the peptide concentration both increased with exercise testing in the nine patients evaluated. We conclude that the release of atrial natriuretic peptide is at least partly regulated by right and left atrial pressures. Distinguishing the relative contributions of the two atria and defining the role of peptide release in the pathogenesis of heart failure will require further investigation.     

Effect of low-dose endurance training on heart rate variability at rest and during an incremental maximal exercise test

We evaluated the effects of low-dose endurance training on autonomic HR control. We assessed the heart rate variability (HRV) of 11 untrained male subjects (36.8 +/- 7.2 years) at rest and during an incremental maximal aerobic exercise test prior to a 7-week preparatory period and prior to and following a 14-week endurance training period, including a low to high intensity exercise session twice a week. Total (0.04-1.2 Hz), low (0.04-0.15 Hz) and high (0.15-1.2 Hz) frequency power of HRV were computed by short-time Fourier transform. The preparatory period induced no change in aerobic power or HRV. The endurance training period increased peak aerobic power by 12% (P < 0.001), decreased the HR (P < 0.01) and increased all HRV indices (P < 0.05-0.01) at absolute submaximal exercise intensities, but not at rest. In conclusion, low-dose endurance training enhanced vagal control during exercise, but did not alter resting vagal HR control.     

Effects of dobutamine and salbutamol on haemodynamics and atrial natriuretic factor in patients with severe congestive heart failure.

The influence of two cardiac inotropic drugs, dobutamine and salbutamol, on plasma atrial natriuretic factor (ANF) was investigated in 20 patients with congestive heart failure. All were in New York Heart Association class-III or IV. The patients underwent right heart catheterization with determination of central pressures, cardiac output, and pulmonary arterial plasma ANF during incremental infusions with dobutamine or salbutamol. Fourteen patients completed the study. Both drugs induced comparable increases in cardiac index and decreases in total systemic vascular resistance (P less than 0.01) without significant changes in central pressures. Heart rate rose after salbutamol (P less than 0.05), but not after dobutamine. No changes in plasma ANF were observed after either of the drug infusions. ANF secretion rate was calculated from simultaneous measurements of ANF in right atrial and pulmonary arterial plasma before and after salbutamol infusion, and median values rose more than seven-fold (P less than 0.05). The results demonstrate that ANF secretion rate is augmented after beta-adrenergic agents, possibly by a direct beta 2-adrenergic stimulation, in patients with severe congestive heart failure, and that changes in plasma ANF are an insufficient measure of ANF release when patient samples are small.